Preparations comprising a fluorocarbon or a highly fluorinated compound and a lipophilic/fluorophilic compound and their uses

ABSTRACT

Fluorocarbon emulsions comprising a stabilizing, particle size controlling fluorophilic/hydrophilic compound which can have the formula 
     
         R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I) 
    
     wherein 
     R F   1  is a linear, branched or cyclic C 2-14  fluorocarbon group; 
     R H   1  is a linear, branched or cyclic C 2-18  saturated or unsaturated hydrocarbon group; and 
     W is absent or is a bivalent species chosen from the group consisting of --O--, --S--, or various fluorinated structures. Use of the fluorophilic/lipophilic compound in the dispersions of the invention provides stable particle size and efficient emulsification. The dispersions of the invention can comprise biologically useful additive and can be used for various purposes, as oxygen carriers, contrast agents, or diagnostic agents.

This application is a continuation of U.S. patent application Ser. No.07/916,216, filed Jul. 17, 1992, now abandoned.

This application claims priority to French application No. 91-09026which was filed Jul. 17, 1991.

The present invention relates to formulations comprising highlyfluorinated or perfluorinated compounds, referred to generally asfluorocarbons. It relates particularly to fluorocarbon emulsionformulations that form emulsions having superior emulsion stability andcontrolled particle sizes.

BACKGROUND OF THE INVENTION

Fluorocarbon compounds and their formulations have numerous applicationsin human and veterinary medicine as therapeutic and diagnostic agents.Fluorocarbons have many potential applications in the biomedical field,as blood substitutes, or more generally, as carriers in applicationswherein oxygen must be supplied to organs and tissues, for example, inthe treatment of cardio- and cerebrovascular disease, angioplasty, inorgan preservation and in cancer therapy. Fluorocarbon formulations arealso useful in diagnostic procedures, for example as contrast agents,and in the field or veterinary therapy (Riess, J. G., HemocompatibleMaterials and Devices: Prospectives Towards the 21st Century, TechnomicsPubl. Co, Lancaster, Pa. USA, Chap 14 (1991); Vox Sanguinis., Vol.61:225-239 (1991). One commercial biomedical fluorocarbon emulsion,Flusol®, (Green Cross Corp., Osaka, Japan), is presently used, forexample, as an oxygen carrier to oxygenate the myocardium duringpercutaneous transluminal coronary angioplasty (R. Naito, K. Yokoyama,Technical Information, Series n° 5 and 7, 1981).

The dispersed phase of fluorocarbon emulsions must have a stableparticle size to be suitable for biomedical use. One of the drawbacks ofthe Fluosol emulsion is its low stability; the particle size offluorocarbon emulsions such as Fluosol® can be maintained only if theyare transported and stored in the frozen state. The frozen emulsions arethen defrosted and mixed with two annex solutions before use. Thesestorage requirements seriously limit the field of application ofFluosol. Although more stable fluorocarbon emulsions are being developed(Oxygent® and Imagent®, Alliance Pharmaceutical Corp., San Diego,Calif.), it is desirable to have fluorocarbon emulsions that are stableenough to store for long periods without refrigeration. Such storagestability would extend the use of fluorocarbons beyond medicalfacilities in order to meet, for example, the requirements of the armyand civil defense. It is also desirable to control particle sizes toadapt the emulsion characteristics to specific applications.

Fluorocarbons are oily substances that are immiscible with water, andtherefore fluorocarbon-in-water emulsions, such as Fluosol® andOxygent®, are presently prepared using lecithins and/or poloxamers ofthe Pluronic F-68® type as surfactants to disperse the fluorocarbon andstabilize the emulsion. Surfactants are commonly amphiphilic compoundshaving a hydrophobic end region and a hydrophilic end region. Lecithinshave a hydrophobic end region comprising a hydrocarbon groups which havea low affinity for fluorocarbons. It is desirable to improve theaffinity of the surfactant film for the fluorocarbon phase and to reducethe interfacial tension between the fluorocarbon and aqueous phases.(Riess, J. G., Competes Rendus du 2^(eme) Congres Mondial des Agents deSurface (Paris, May 1988), ASPA 4:256-263 (1988)).

Several strategies can be employed to overcome this disadvantage of theemulsifying surfactants described. One approach is to develop moreeffective surfactants, for example, those having a hydrophobic end whichis fluorophilic, for use in the preparation of classic emulsions.Efforts in this direction have led to new fluorinated surfactants suchas those described in the documents EP-A- 0 255 443, EA-A-A 0 311 473and WO 90/15807.

Another strategy is to prepare microemulsions, i.e., preparations ofcompounds which organize themselves spontaneously into dispersed systems(H. L. Rosano and W. E. Gerbacia, U.S. Pat. No. 3,778,381, Dec. 11,1973; and G. Mathis, J. J. Delpuech, FR-A-2 515 198, 3.29.1983). In anexample of a microemulsion described by Cecutti et al. Eur. J. Med.Chem., 24, 485-492 (1989), the dispersed phase is itself totallyconstituted of mixed hydrocarbon/fluorocarbon molecules. However, thisstrategy is not generally applicable to fluorocarbons, particularlythose of the examples described in the present invention. Moreover, itis still totally uncertain whether the intravenous administration ofmicroemulsions is safe. To our knowledge, no example of suchadministration exists in human medicine, whereas the classicalemulsions, such as the lipidic emulsions for parenteral nutrition areabundantly used.

It would be advantageous to be able to emulsify any fluorocarbon chosensolely on the basis of its own advantageous properties and its efficacy,without regard to the problem of emulsification. For example, it wouldbe advantageous to be able to prepare stable emulsions of perfluorooctylbromide (PFOB, perflubron®, Alliance Pharmaceutical Corp., La Jolla,Calif.) on account of its radiopacity, and of its potential as acontrast agent in diagnostics. It would also be advantageous to set theparticle size in the emulsion at a value chosen a priori.

SUMMARY OF THE INVENTION

The invention comprises preparations of dispersions, emulsions, and gelscomprising a highly fluorinated compound or fluorocarbon, a surfactant,a lipophilic/fluorophilic organic compound, and an aqueous phase,methods of manufacturing the preparations, and their uses. Thepreparations of the invention comprise an amphiphilic organicfluorophilic-lipophilic compound of the formula R_(F) ¹ --W--R_(H) ¹wherein R_(F) ¹ is a fluorinated hydrocarbon radical and R_(H) ¹ is ahydrocarbon radical as defined herein and W is absent or is --O--,--S--, or a hydrocarbon group having fluorinated regions as definedherein.

The lipophilic/fluorophilic compound of the invention can be a branchedchain structure comprising hydrocarbon groups and fluorinatedhydrocarbon groups, as for example, formulas (II) and (III). Thefluorinated hydrocarbon groups of the compound can be furthersubstituted by Br and Cl in addition to F. In a preferred embodiment ofthe invention, the lipophilic/fluorophilic compound is of the formula

    CF.sub.3 (CF.sub.2).sub.t1 --(CH.sub.2).sub.t2 --CH═CH--(CH.sub.2).sub.y --CH.sub.3

wherein t₁ =2 to 11, t₂ =0 or 1 to 6 and y=1 to 15.

The lipophilic/fluorophilic compound is advantageously constituted ofone or more essentially hydrocarbon fragments of the formula (II)described below and one or more highly fluorinated fragments, typicalexamples of such compounds being the molecules CF₃ (CF₂)_(t) (CH₂)_(y)CH₃ or

    CF.sub.3 (CF.sub.2).sub.t1 --(CH.sub.2).sub.t2 --CH═CH--(CH.sub.2).sub.y --CH.sub.3

The preparations of the invention further comprise a surfactant selectedfrom a lecithin, a lecithin analog, or the perfluoroalkylatedsurfactants. The proportions of the components of the preparations arepreferably from about 10 to 130% weight/volume of afluorocarbon-containing phase; from 0.05 to 10% weight/volume of asurfactant; and from about 0.1 to 50% weight/volume of thefluorophilic/lipophilic compound in a suitable aqueous phase.

The emulsions can further comprise any additive suitable to enhance thepurpose of the formulation, such as mineral salts, buffers,pharmaceuticals, nutrients, or diagnostic agents. The fluorocarbon canbe any suitable fluorocarbon compound, but preferably those molecularspecies disclosed herein.

The preparations of the invention are prepared by adding an appropriatequantity of the fluorophilic/lipophilic compound to the fluorocarbon orto the aqueous phase prior to emulsification to achieve the desiredfinal concentration of the compound in the emulsion. The addition of thefluorophilic/lipophilic compound acts to bring the emulsion particles toa desired size more rapidly, and to stabilize the emulsion againstchanges in particle size on storage. The stabilizing effect isrelatively independent of storage temperature.

The preparations can have various forms: dispersions, emulsions or gels,and can be used for various purposes, as oxygen carriers, drug carriersor as contrast agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the change in the average diameters (in μm) ofparticles of perfluorooctyl bromide (PFOB; perflubron®) emulsionsconforming to the invention and comprising the fluorophilic/lipophiliccompound C₆ F₁₃ CH═CHC₈ H₁₇ :F6H8E, and of particles of a referenceemulsion, prepared without F6H8E, as a function of time (in days) duringaging, at 25° C. or 40° C.

FIG. 2 represents the change in the average diameters (in μm) ofparticles of perflubron® emulsions of the invention comprising thefluorophilic/lipophilic compound C₈ F₁₇ CH═CHC₈ H₁₇ :F8H8E, and ofparticles of a reference emulsion, prepared without F8H8E, as a functionof time (in days) during aging at 40° C.

FIG. 3 represents the change in the average diameters (in μm) ofparticles of perfluorooctyl bromide emulsions of the inventioncomprising the fluorophilic/lipophilic compound F8H10, and of particlesof a reference emulsion, as a function of time (in days) during aging at40° C.

FIG. 4 represents the change in the average diameters (in μm) ofparticles of perfluorooctyl bromide (perflubron) emulsions of theinvention comprising the lipophilic/fluorophilic compound C₈ F₁₇ CH═CHC₈H₁₇ (F8H8E), and particles of a reference emulsion prepared withoutF8H8E, as a function of time (in days) during aging at 40° C.

FIG. 5 represents the change in the average diameter (in μm) ofparticles of perfluorooctyl bromide (perflubron™) emulsions of theinvention comprising the fluorophilic/lipophilic compound C₆ F₁₃ C₁₀ H₂₁(F6H10), and of particles of a reference emulsion prepared withoutF8H10, as a function of time (in days) during aging at 40° C.

FIG. 6 represents the change in the actual diameters (in μm) ofparticles of perfluorooctyl bromide (perflubron™) emulsions of theinvention comprising the fluorophilic/lipophilic compound C₈ F₁₇ CH═CHC₈H₁₇ (F8H8E) in 0.7% w/v amount, and of particles of a reference emulsionprepared without F8H8E, as a function of time (days) during aging at 40°C.

FIG. 7 represents the change in the average diameters (in μm) ofparticles of 1,2-bis-(F-butyl)ethene (F-44E) emulsions of the inventioncomprising the fluorophilic/lipophilic compound C₈ F₁₇ CH═CHC₈ H₁₇(F8H8E), and of particles of a reference emulsion prepared withoutF8H8E, as a function of time (in days) during aging at 40° C.

FIG. 8 represents the change in the average diameters (in μm) ofparticles of perflubron® emulsions of the invention comprising thefluorophilic/lipophilic compound C₆ F₁₃ C₁₂ H₂₅ (F6H12), and ofparticles of a reference emulsion prepared without F6H12, as a functionof time (in days) during aging at 40° C.

FIG. 9 demonstrates the effect of F8H8E (Dowel structure, C₈ F₁₇ CH═CHC₈H₁₇), on PFOB emulsion particle size and particle size stability, as afunction of the number of passes, and the influence of adding F8H8E onthe percentage of particles (a) smaller than 0.12 μm and (b) larger than0.6 μm.

⋆: Change in mean particle diameter d without F8H8E;

★: change in mean particle diameter d with F8H8E;

Δ: percent of particles <0.12 μm diameter with F8H8E;

□: percent of particles <0.12 μm diameter without F8H8E;

▴: particles >0.6 μm without F8H8E;

▪: percent of particles >0.6 μm with F8H8E.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to forming substantially stabledispersed preparations, whether in the form of dispersions, emulsions orgels, through the use of additives that improve the stability ofemulsions wherein the hydrophobic or oily phase of the preparationcontains a highly fluorinated compound or a perfluorocarbon compound,prepared using classical surfactants. The additives also provide a tightcontrol of particle size.

Definitions:

Perfluorocarbon is an analogue of a hydrocarbon which is highlyfluorinated, having at least half of the hydrogen atoms replaced byfluorine atoms, or perfluorinated, having all of the hydrogen atomsreplaced by fluorine atoms.

Hydrocarbon radical, hereinafter R_(H), is a linear, branched or cyclic,saturated, monosaturated or polyunsaturated hydrocarbon group, whereinthe unsaturated bonds are ethylenic or acetylenic. In these groups, oneor more atoms of the carbon chain can be replaced by other bivalentspecies, such as O or S.

Fluorinated hydrocarbon radical, hereinafter R_(F), is a linear,branched, or cyclic hydrocarbon group which is highly fluorinated,having at least half of the hydrogen atoms replaced by fluorine atoms,or perfluorinated, having all of the hydrogen atoms replaced by fluorineatoms. Some of the fluorine atoms can be replaced by Cl and Br; one ormore atoms of the carbon chain can be replaced by other bivalentspecies, such as O or S.

Fluorophilic/lipophilic compound is an amphiphilic molecule having afluorinated hydrocarbon structure, as defined above, linked to asubstantially hydrocarbon structure, as defined above, of theconventional composition of carbon and hydrogen.

Preparations according to the invention accordingly comprise (1) an oilyor hydrophobic phase comprising at least one highly fluorinated compoundor perfluorocarbon; (2) a continuous phase; (3) at least oneconventional surfactant; and (4) an amphiphilic organic compound havinga fluorophilic region comprising a fluorinated hydrocarbon radical and alipophilic region, comprising a hydrocarbon radical.

According to a preferred embodiment of the invention, the dispersedpreparation is of the oil-in-water type wherein the hydrophobic phasecontaining the fluorocarbon or highly fluorinated compound is dispersedin a continuous aqueous phase.

According to one embodiment of the invention, the organicfluorophilic-lipophilic compound is of the formula:

    R.sub.F.sup.1 --W--R.sub.W.sup.1                           (I)

wherein

R_(F) ¹ is a linear, branched or cyclic C₂₋₁₄ fluorocarbon group;

R_(H) ¹ is a linear, branched or cyclic C₁₋₁₈ saturated or unsaturatedhydrocarbon group; and

W is absent or is a bivalent species chosen from the group consisting of--O--, --S--, or is of the formula: ##STR1## wherein X¹, X² and X³ areabsent or are independently selected from the group consisting of --O--,or --S--;

R_(F) ² is a fluorocarbon independently selected from the group definedfor R_(F) ¹ ;

R_(H) ² is a hydrocarbon independently selected from the group definedfor R_(H) ¹ ; and

R² is absent or is a fluorocarbon or a hydrocarbon independentlyselected from the group defined for R_(F) ¹ or R_(H) ¹ ; and

p and q are independently 1-10.

In yet other embodiments, the carbon chain of the R_(H) ¹ or R_(H) ²region of the fluorophilic-lipophilic compound can contain a substituentselected from the group consisting of --O-- and --S--, wherein R¹ is alinear or branched C₁₋₁₂ alkyl group.

According to another embodiment of the invention, the organicfluorophilic/lipophilic compound is of the formula: ##STR2## wherein X4is --O--, --S-- or --S--S; and

a1 and a2 are independently from 0 to 11.

According to yet another embodiment of the invention, the organicfluorophilic/lipophilic compound is of the formula: ##STR3## wherein X⁵is --O--, --S--, or --S--S--;

p and q are independently from 1 to 10;

R_(F) ¹ and R_(F) ² are independently selected from a group ofperfluroralkylated radicals having from 2 to 10 carbon atoms, and R_(H)³ is selected from the group of hydrocarbon radicals having from 2 to 16carbon atoms.

The preparations of the invention, whether in the form of a dispersion,an emulsion or a gel, comprise a substantially aqueous phase which isnot miscible with the oily phase, as well as at least one natural orsynthetic surfactant, in particular a hydrophilic-lipophilic surfactantsuch as those generally used for the preparation of dispersions,emulsions or gels. Examples of such surfactants are lecithins,perfluoroalkylated surfactants, and their mixtures.

The fluorocarbon dispersions to which the compositions of the inventionare directed are distinct from the conventional oil-in-water emulsionsin their physical complexity. Oil particles are held dispersed inconventional emulsions and dispersions by virtue of a surfactantmolecule, which is a molecule having an amphipathic structure comprisinga lipophilic region, such as a hydrocarbon structure which has affinityfor fatty substances which are also mainly hydrocarbons, and alsocomprising a hydrophilic or polar region, which has affinity for thepolar water molecules of the aqueous phase. Without a surfactant, thewater immiscible oil phase would separate rapidly from the aqueous phasein the presence of water. The surfactant acts to lower the interfacialtension between the aqueous phase and the lipid phase and to build aninterfacial film around each droplet of the dispersed phase, whichstabilizes the emulsion.

Fluorocarbons are heavy water immiscible liquids which are like oilysubstances except that they are neither hydrophilic nor lipophilic. Thusthe interfacial tension between fluorocarbon liquids and an aqueousphase cannot be effectively reduced by conventional surfactants.However, an amphiphilic system that is analogous to a conventionallipophilic/hydrophilic surfactant, but having fluorophilic/hydrophilicregions is preferable. This system is structured, according to thepresent invention by using, in combination, paired molecules comprisinga conventional surfactant and a fluorophilic/lipophilic molecule, whichact together in association to reduce the interfacial tension andstabilize the dispersion.

In this case, the addition of compound R_(F) ¹ --W--R_(H) ¹ which bearsboth a lipophilic hydrogenated part (R_(H) ¹) and a fluorophilicfluorinated part (R_(F) ¹) facilitates the adhesion of the aqueous phaseto the oily, fluorocarbon-based phase of the dispersion, emulsion orgel, by interaction of this compound with the lipophilic part of thehydrophilic-lipophilic surfactant.

In such preparations, indeed, the conventional hydrophilic-lipophilicsurfactant of the one hand, and the R_(F) ¹ --W--R_(H) ¹ compound of theother hand, constitute two distinct types of molecules whosecontributions are complementary and assure to the conventionalsurfactant a good aqueous/lipidic membrane phase interaction, and thelatter (R_(F) ¹ --W--R_(H) ¹ compound) a good lipidicmembrane/fluorocarbon interaction.

This can be illustrated schematically in terms of synergistic surfactanteffects as follows:

    ______________________________________                                        Surfactant                                                                    Effect   Water                Fluorocarbon                                    ______________________________________                                        (1)      hydrophilic <-->                                                                           lipophilic                                              (2)                   lipophilic <-->                                                                           fluorophilic                                ______________________________________                                    

Contribution (1) is furnished by the hydrophilic-lipophilic surfactantand contribution (2) by the lipophilic-fluorophilic compound, forexample of formula R_(F) ¹ --W--R_(H) ¹, in conformity with theinvention.

The R_(F) ¹ --W--R_(H) ¹ compounds are generally very unreactive andnontoxic, and thus suitable for biomedical applications. Their use inthe formulations of the invention eliminates the need to use othersurfactants whose biocompatibility must be tested. The desired effectcan also be obtained by using small quantities of R_(F) ¹ --W--R_(H) ¹.

According to the invention, the fluorophilic chain of compound R_(F) ¹--W--R_(H) ¹ which corresponds to R_(F) ¹, and in some cases to R_(F) ²,is a straight or branched fluorinated hydrocarbon radical, of 2 to 14carbon atoms, which may bear oxygen atoms and/or other substituents forexample, Cl.

Examples of fluorinated radicals that can be used are:

CF₃ (CF₂)_(t) -- wherein t=1 to 11;

(CF₃)₂ CF(CF₂)_(v) -- wherein v=0 to 8;

CF₃ (CF₂ CF(CF₃))_(w) -- wherein w=1 to 4;

C₂ F₅ (CF₂ CF(CF₃))_(w) -- wherein w=1 to 4;

(CF₃)₂ (CFCF₂ CF(CF₃))_(w) -- wherein w=1 to 3; and ##STR4## wherein x=1to 6; and R_(F) ¹ and R_(F) ² are independently chosen from the groupconsisting of CF₃ --, C₂ F₅ --, n--C₃ F₇ --, n--C₄ F₉, and CF₃ CF₂CF(CF₃)--; or R_(F) ¹ and R_(F) ² together form a bivalent radicalchosen from the group consisting of:

--CF₂ (CF₂)₂ CF₂ --

--CF₂ (CF₂)₃ CF₂ --; and

--CF₃ CF₂ O--(CF₂ CF₂ O)_(y) --CF₂ --

wherein y=0 to 3; and

CF₃ (CF₂)₂ O--(CF(CF₃))(CF₂ O)_(y) --CF(CF₃)--

wherein y=0 to 2.

Among the fluorinated radicals corresponding to the above formulas, theradical of formula CF₃ (CF₂)_(t), in which t is a whole number from 1 to11, and preferably from 3 to 9, are particularly useful.

According to the invention, the lipophilic part of compound R_(F) ¹--W--R_(H) ¹, represented by R_(H) ¹ and possibly R_(H) ² is a linear,branched or cyclic, saturated or unsaturated, hydrocarbon radical, offrom 1 to 18 carbon atoms, which may bear in its chain 1 or severalgroups.

Examples of radicals from among which R_(H) ¹ and R_(H) ¹ can be chosenare:

(a) CH₃ --(CH₂)_(y1) -- wherein y₁ =1 to 17;

(b) CH₃ (CH₂)_(y2) (CH═CH)q(CH₂)_(y3) -- CH₃ (CH₂)_(y2) --CON(R_(H)¹)--(CH₂)_(y3) 13 CH₃ (CH₂)_(y2) --S--(CH₂)_(y3) -- and CH₃ (CH₂)_(y2)--N(R_(H) ¹)--(CH₂)_(y3) -- wherein y₂ and y₃ are independently 1 to 16,q=0 or 1,and R_(H) ¹ is as defined above;

(c) CH₃ (CH₂ --CH₂ --O)_(y4) --CH₂ wherein y4=1 to 8; and

(d) CH₃ (CH(CH₃)CH₂ O)_(y5) --CH--CH₃ wherein y5=1 to 5.

According to a particularly preferred embodiment of the invention, incompound R_(F) ¹ --W--R_(H) ¹ :

R_(H) ¹ is R⁴ --CH═CH--(CH₂)_(p) -- wherein R⁴ is a linear alkylatedradical of 2 to 12 carbon atoms, and p is equal to 0 or is a wholenumber from 1 to 8, and

W is a single bond.

Examples of compounds R_(F) ¹ --W--R_(H) ¹ that can be used in thisembodiment of the invention are:

CF₃ (CH₂)_(t1) --(CH₂)_(t2) --CH═CH--(CH₂)_(y6) --CH₃

in which t₁ is a whole number from 2 to 11, t₂ is a whole number from 0to 6 and y₆ is a whole number from 1 to 15.

These compounds can be prepared by classical procedures, for example, byaddition of a perfluoroalkylated iodide of formula CF₃ --(CH₂)_(t1)(CH₂)_(t2) I to an olefin of formula CH₃ --(CH₂)_(y6) --CH═CH₂, followedby dehydroiodation (J. Org. Chem. 27:26261 (1962) and J. Org. Chem.37:24-29 (1972)).

Examples of compounds corresponding to the above formula are those inwhich t₁ =3,5 or 7, t₂ =0, and y₆ =3,5,7 or 9.

These compounds are of much interest, as they are of low toxicity.Intraperitoneal injection of such compounds into mice at a dose of 25mL/kg body weight showed no toxicity. Intravascular injection of suchcompounds in the form of an emulsion (F6H10E/EYP 25/6% w/v) into rats iswell tolerated by the animals (no death resulted among 33 animals givena 15 ml/kg body weight dose). The half retention time in liver forF6H10E is about 24 days (to be compared with 65 days forperfluorotripropylamine).

According to a preferred embodiment of the invention, the R_(H) ¹ moietyof compound R_(F) ¹ --W--R_(H) ¹, is a linear alkylated radical of 4 to12 carbon atoms, and

W is a single bond.

Examples of compounds R_(F) ¹ --W--R_(H) ¹ that are useful in thissecond embodiment of the invention are the semi-fluorinated n-alkaneswhich can be prepared by the procedures described by Rabolt et al. inMacromolecules, 17(12), 2786-2794 (1984) or by Twieg et al. in Polym.Prep., 25, 154-5 (1984).

According to other embodiments of the invention, the R_(H) ¹ moiety ofthe compound R_(F) ¹ --W--R_(H) ¹ is an alkylated, linear radical of C4to C12, and

W is a group of one of the following formulas: ##STR5## in which X¹, X²,X³, R_(H) ², R_(F) ², and R² are defined as above.

In these different embodiments of the invention, R_(F) ¹ is preferably aperfluorinated linear radical of formula CF₃ (CF₂)_(t), and t is a wholenumber from 1 to 11.

Compounds R_(F) ¹ --W--R_(H) ¹ which correspond to these differentembodiments of the invention can be prepared by classical procedures. Inthe preparations of the invention, the fluorocarbons constituting theoily phase can be linear or cyclic compounds, with molecular weightspreferably from 400 to 700, and they can be chosen, for example, fromamong perfluorodecalin, 1,2-bis(F-alkyl)ethenes,1,2-bis(F-butyl)ethenes, 1-F-isopropyl, 2-F-hexylethenes and1,2-bis(F-hexyl)ethenes, perfluoromethyldecalins,perfluorodimethyldecalins, perfluoromethyl-,and dimethyladamantanes,perfluoromethyl-dimethyl- and trimethylbicyclo (3,3,1) nonanes and theirhomologs, perfluoroperhydrophenanthrene, ethers of formulae: (CF₃)₂CFO(CF₂ CF₂)₂ OCF(CF₃)₂, (CF₃)₂ CFO(CF₂ CF₂)₃ OCF(CF₃)₂, (CF₃)₂ CFO(CF₂CF₂)₂ F, (CF₃)₂ CFO(CF₂ CF₂)₃ F, F[CF(CF₃)CF₂ O]₂ CHFCF₃, [CF₃ CF₂ CF₂(CF₂)u]₂ O with u=1, 3 or 5, amines N(C₃ F₇)₃, N(C₄ F₉)₃, N(C₅ F₁₁)₃,perfluoro-N-methylperhydroquinolines andperfluoro-N-methylperhydroisoquinolines, perfluoralkyl hydrides such asC₆ F₁₃ H, C₈ F₁₇ H, C₈ F₁₆ H₂ and the halogenated derivatives C₆ F₁₃ Br,(perflubron), C₆ F₁₃ CBr₂ CH₂ Br, 1-bromo 4-perfluoroisopropylcyclohexane, C₈ F₁₆ Br₂, CF₃ O(CF₂ CF₂ O)_(u) CF₂ CH₂ OH with u=2 or 3.These compounds can be used alone or in mixtures.

In preparations in the form of dispersion, emulsions or gels, thesurfactants used generally comprise a hydrophilic part and a hydrophobicpart, and can consist of fluorinated or non-fluorinated surfactants.Preferably, classical surfactants are used, such as those usuallyemployed in preparations for biomedical use, for example, phospholipidsand poloxamers such as copolymers of polyoxyethylene-polyoxypropylenetype, such as Pluronic F-68®, and their mixtures.

When the preparation of the invention is in the form of a dispersion, anemulsion or a gel and comprises an aqueous phase and at least onesurfactant, its composition in generally in the following ranges:

from 10 to 130% in weight/volume of oily phase;

from 0.1 to 10% in weight/volume of surfactant(s); and

from 0.01 to 50% in weight/volume of lipophilic-fluorophilic organiccompound(s), the rest being constituted by the aqueous phase.

In a preferred embodiment, the composition contains from 0.01% to 10% ofa lipophilic/fluorophilic organic compound or a mixture of suchcompounds.

The preparations in the form of emulsions can be made by the classicalprocedures generally used to prepare emulsions. For example, suchpreparations can be made by dispersing the surfactant(s) and the R_(F) ¹--W--R_(H) ¹ compounds in an aqueous phase which may contain otheradditives, then adding the oily phase to this dispersion and emulsifyingthe whole mixture by classical techniques. Appropriate techniques aredescribed, for example, in EP-A- 0 231 070 and EP-A- 307 087. CompoundR_(F) ¹ --W--R_(H) ¹ can also be added to the oily phase before mixingthe two phases.

The lipophilic/fluorophilic compounds used in the invention achieveemulsion particle size stability when added to 90/4% w/v PFOB/EYPemulsion. These compounds retain particle size at 0.13 μm aftersterilization, and maintain this particle size for 3 months as 40° C.(FIGS. 2, 3, and Table II). By comparison, the reference emulsioncontaining only PFOB/EYP grows from 0.15 μm after sterilization to 0.32μm after 3 months at 40° C. The same phenomenon of stabilization isobserved when the compounds used in the present invention are added toF-44E/EYP 90/4% w/v emulsions; the particle size stays at 0.14 μm aftersterilization, and after 3 months at 40° C. By comparison, the particlesize diameter in the reference emulsion increases from 0.15 μm to 0.32μm (FIGS. 7, 8, Table III).

The lipophilic/fluorophilic compounds used in the invention also allowone to control emulsion particle size and particle size stability. Theadjustment of particle size in obtained by adjusting, for a given amountof fluorocarbon, the total amount of the mixture oflipophilic/fluorophilic compound and lecithin; for example, the particlesize is about 0.23 μm when a 90% w/v emulsion of perfluorooctyl bromideis stabilized using a mixture consisting of 2% w/v of EYP and 1.4% w/vof F8H8E (FIG. 4); or the particle size is about 0.38 μm when the 90%w/v emulsion of perfluorooctyl bromide is stabilized using a mixtureconsisting of 1% w/v of EYP and 0.7% w/v of F8H8E (FIG. 6); or theparticle size is about 1.5 μm when a 90% w/v emulsion of perfluorooctylbromide is stabilized using a mixture consisting of 0.2% w/v of EYP andan equimolar amount of F8H8E; or the particle size is about 2.75 μm whena 90% w/v emulsion of perfluorooctyl bromide is stabilized using amixture consisting of 0.1% w/v EYP and an equimolar amount of F8H8E, andso forth.

The effective ratio of the amount of the lipophilic/fluorophilic "dowel"compounds of the invention to the amount of surfactant is independent ofboth the nature or species of the fluorocarbon molecule and theconcentration of the fluorocarbon in the emulsion. The effectivedowel/surfactant ratio has been found to be in the molar ratio ofbetween about 1/10 and 10/1, with a preferred molar ratio of 1/1. Thisbroad range of effective dowel/surfactant molar ratios was determined instudies using several different fluorocarbon species, for example,F-decalin, perfluorooctyl bromide (perflubron®), and F44-E, in emulsionshaving fluorocarbon concentrations of from about 20% w/v to 100% w/v,and containing an amount of EYP surfactant varying from about 1 to 8%w/v. This comprises a 10⁻³ to 10⁻⁴ M concentration of the EYPsurfactant, and equivalent mole concentrations of other surfactants werefound to be similarly effective. The molar ratio of dowel/EYP shown tobe effective in these studies was 1/5, 1/3, 1/1, 2/1 and 3.1.

The compounds used in the methods of the invention facilitate theformation of the emulsion and lead to emulsions with fine particle sizeafter a reduced number of passes or a reduced amount of energy. When thecompound F8H8E of the invention is added to perfluorooctylbromide/lecithin emulsion, 30% of fine particles are obtained after 10passes. By comparison, the reference emulsion without the compounds ofthe invention requires 20 passes to obtain the same percentage of fineparticles (FIG. 9).

The preparations of the invention, whatever their form (dispersions,emulsions or gels), can also comprise other additives, for example thosegenerally used in emulsions, such as mineral salts, buffers, osmoticagents, oncotic agents, nutritive agents, or other ingredients that helpto improve the characteristics, the stability, the efficacy and thetolerance of the emulsions.

The preparations of the invention can be used in the pharmaceuticalfield as medicaments in the form of emulsions or dispersionsadministrable, for example, orally or through the trachea, or byinjection into the blood stream or into other cavities or organs of thebody.

The preparations of the invention can also be used in pharmacy,cosmetics, in the veterinary or phytosanitary fields, in biology andmedicine, in particular as oxygen carriers that can be employed, amongother uses, as blood substitutes, or more generally for theadministration of oxygen. Certain preparations of the invention can alsobe used as contrast agents to facilitate diagnosis, particularly byradiography, sonography or nuclear magnetic resonance imagery. Thepreparations, gels, emulsions or other dispersions of the invention canbe used as media for treating cerebral and cardiac ischemia, forperi-operative hemodilution, for the preservation of organs, tissues,embryos, semen, as media to be used in cardiovascular therapy andsurgery, for example as cardioplegic or reperfusion solutions, or incoronary angioplasty, media serving as an adjuvant in radiotherapy andchemotherapy of cancer, or as drug vehicle.

Other characteristics and advantages of the invention will be betterseen in the following examples and in FIGS. 1-9. The present inventionis described in detail using the following examples; however, thesepreferred embodiments are to be construed as merely illustrative and notlimitative of the remainder of the disclosure in any way whatsoever.

In these examples, the lipophilic-fluorophilic R_(F) ¹ --W--R_(H) ¹compound is of the formula:

    CF.sub.3 (CF.sub.2).sub.t --(CF═CH).sub.y --(CH.sub.2).sub.y CH.sub.3, or CF.sub.3 (CF.sub.2).sub.t --(CH.sub.2).sub.y CH.sub.3

and is designated hereinafter generally as F_(t+1) H_(y+1) E_(v), orF_(t+1) H_(y+1), respectively, and specifically as:

F6H8E when t=5 and y=7, v=1;

F8H8E when t=7 and y=7, v=1;

F6H6E when t=5 and y=5, v=1;

F6H10 when t=5 and y=9, v=0.

EXAMPLES 1, 2 AND 3 Stabilization of an Emulsion of PerfluorooctylBromide/Lecithin 90/4% in Weight Per Volume (w/v) using a Compound R_(F)WR_(H).

Reference Emulsion A:

Emulsions of Perflubron/Lecithin (90/4% w/v)

32 g of egg-yolk lecithin and a mixture of salts whose composition isshown in detail in Table I was dispersed with Ultra Turrax undernitrogen (24000 t/min, 10 min) in 383 mL of injectable water.Perfluorooctyl bromide (PFOB, perflubron®) (375 mL) was added slowly tothis dispersion under nitrogen. The mixture was dispersed for 10 mn at30-40° C. The coarse emulsion obtained was passed under nitrogen througha microfluidizer (M110F). After 10 passes under a pressure of 12000 psiin the chambers cooled to 35° C., the emulsion was recovered, filled inflasks then sterilized at 121° C. for 15 mn. The ageing was monitored at5,25 and 40° C. (Table II and FIG. 1) and the average size of theparticles measured by photosedimentation.

                  TABLE I                                                         ______________________________________                                        Composition of reference emulsion A (for 100 mL).                             ______________________________________                                        PFOB                  90 g                                                    Lecithin              4 g                                                     NaCl                  0,3 g                                                   EDTACaNa2             0,02 g                                                  NaHPO.sub.4 --Na.sub.2 PO.sub.4                                                                     35 mM                                                   α-Tocophero1    0,002 g                                                 H.sub.2 O for injection                                                                             qsp 100 ml                                              ______________________________________                                    

Example 1 Stabilization of an Emulsion of PerfluorooctylBromide/Lecithin by Addition of C₆ F₁₃ CH═CHC₈ H₁₇ (F6H8E)

32 g of egg-yolk lecithin and a mixture of salts of the abovecomposition (Table I) was dispersed under nitrogen using an Ultra TurraxT50 (24000 t/min, 10 min) in 379 mL of injectable water at 30-40° C.F6H8E (14.3 mL) was slowly added to this dispersion, which was stirredfor 2 min. Perfluorooctyl bromide (375 mL) was then slowly added. Thewhole was emulsified for 10 min at 24000 t/min at 30-40° C. The coarseemulsion obtained was run under nitrogen through the microfluidizer andafter 10 passes (12000 psi, 35° C.) the emulsion was filled in vials,sterilized and stored at 5,25 and 40° C. (Table II and FIG. 1).

The composition of this emulsion was the same as above but for thepresence of F6H8E (2.34 g)

Example 2 Stabilization of the Emulsion of PerfluorooctylBromide/Lecithin by Addition of C₈ F₁₇ CH═CHC₈ H₁₇ (F8H8E)

The protocol described in example 1 was used with 377 mL of water, 16.3mL of F8H8E and 375 mL of perfluorooctyl bromide. Aftermicrofluidization the emulsion was sterilized and stored at 40° C.(Table II and FIG. 2).

Example 3 Stabilization of an Emulsion of PerfluorooctylBromide/Lecithin by Addition of C₈ F₁₇ C₁₀ H₂₁ (F8H10)

The protocol described in example 1 and 2 was used with 377 mL of water,22.4 g of F8H10 and 375 mL of perfluorooctyl bromide. Aftermicrofluidization the emulsion was sterilized and stored at 40° C.(Table II and FIG. 3).

EXAMPLES 4 AND 5 Stabilization of an Emulsion of PerfluorooctylBromide/Lecithin 90/2% in Weight Per Volume (w/v) Using a Compound R_(F)WR_(H).

Reference Emulsion B: Emulsions of Perfluorooctyl Bromide/Lecithin(90/2% w/v)

The same protocol described in the example of Reference A, was used butfor 16 g of egg-yolk lecithin. The aging was monitored at 40° C. (TableII and FIG. 4).

Example 4 Stabilization of an Emulsion of PerfluorooctylBromide/Lecithin by Addition of C₈ F₁₇ CH═CHC₈ H₁₇ (F8H8E)

The protocol described in example 1 was used with 385 mL of water, 8.38mL of F8H8E, 16 g of lecithin and 375 mL of perfluorooctyl bromide.After microfluidization, the emulsion was sterilized and stored at 40°C. (Table II and FIG. 4).

Example 5 Stabilization of the Emulsion of PerfluorooctylBromide/Lecithin by Addition of C₆ F₁₃ C₁₀ H₂₁ (F6H10)

Perflubron

The protocol described in example 1 was used with 392 mL of water, 7,53mL of F6H10, 32 g of lecithin and 375 mL of perfluorooctyl bromide.After microfluidization the emulsion was sterilized and stored at 40° C.(Table II and FIG. 5).

EXAMPLE 6 Stabilization of an Emulsion of Perfluorooctyl Bromide(PFOB)/Lecithin 90/1% in Weight Per Volume (w/v) Using a Compound R_(F)WR_(H).

Reference Emulsion C: Emulsions of Perfluorooctyl Bromide/Lecithin(90/1% w/v)

The same protocol described in example of reference A was used but for 8of egg-yolk lecithin. The aging was monitored at 40° C. (Table II andFIG. 6) and the average size of the particles was measured byphotosedimentation.

Example 6 Sterilization of an Emulsion of PerfluorooctylBromide/Lecithin/Water by Addition of C₈ F₁₇ CH═CHC₈ H₁₇ (F8H8E)

The protocol described in example 1 was used with 382 mL of water, 4,19mL of F8H8E, 8 g of lecithin and 375 mL of perfluorooctyl bromide. Aftermicrofluidization the emulsion was sterilized and stored at 40° C.(Table II and FIG. 6).

                                      TABLE II                                    __________________________________________________________________________    Comparison of stability over time, at 40° C., of                       perfluorooctyl bromide/lecithin 90/4% w/v of various                          formulations containing R.sub.f WR.sub.H and without [as measured by          mean                                                                          diameter, d, of emulsion particles in μm].                                                                   after 3                                     Formulation of emulsions                                                                    at    after  after 12                                                                             months                                      PFOB/lecithin/R.sub.f WR.sub.H % w/v                                                        preparation                                                                         sterilization                                                                        days at 40° C.                                                                at 40° C.                            __________________________________________________________________________    Ref A: 90/4/0 0.14  0.15   0.17   0.32                                        Example 1: 90/4/2.34 (F6H8E)                                                                0.12  0.13   0.15   0.15                                        Example 2: 90/4/2.85 (F8H8E)                                                                0.10  0.13   0.13   0.13                                        Example 3: 90/4/2.8 (F8H10)                                                                 0.11  0.13   0.14   0.14                                        Ref B: 90/2/0 0.13  0.24   0.29   0.36                                        Example 4: 90/2/1.4 (F8H8E)                                                                 0.20  0.25   0.28   0.28                                        Example 5: 90/2/1.4 (F6H10)                                                                 0.17  0.22   0.25   0.25                                        Ref C: 90/1/0 0.20  0.40   0.42   0.47                                        Example 6: 90/1/0.7 (F8H8E)                                                                 0.20  0.40   0.41   0.40                                        __________________________________________________________________________

It is seen that the addition of small quantities of compounds of thetype R_(F) --W--R_(H) to the formula of concentrated fluorocarbonemulsions results in strong stabilization. The size of the fluorocarbondroplets increases significantly more slowly (compare in particular theaverage diameters of the droplets after 12 days and 3 months) in theemulsions containing these mixed hydrocarbon/fluorocarbon compounds thanin the reference emulsions which contain none. These results are alsoillustrated in FIGS. 1, 2, 3, 4 and 5. It is also noteworthy fromexample 4, 5 and 6 that the average particle size can be adjusted, andremains constant over a significant period of time, by adjusting theamount of EYP+mixed hydrocarbon fluorocarbon compound present in theformulation.

EXAMPLES 7 AND 8 Stabilization of an Emulsion of1,2-Bis(F-Butyl)Ethylene/Lecithin 90/4% in Weight Per Volume (w/v) Usinga Compound R_(F) WR_(H).

Reference D: Emulsions of 1,2-Bis(F-Butyl)Ethene (F-44E)/Lecithin/(90/4%w/v)

4 g of egg-yolk lecithin and a mixture of salts whose composition wasshown below are dispersed with Ultra Turrax under nitrogen (24000 t/min,10 min) in 41.16 mL of injectable water. 1,2-Perfluorobutylethene(F-44E) (54 mL) was added slowly to this dispersion under nitrogen. Themixture is dispersed for 10 mn at 30-40° C.

The coarse emulsion obtained is transferred under nitrogen into amicrofluidizer (M110F). After 12 passes under a pressure of 12000 psi inthe chambers cooled to 35° C., the emulsion was recovered, placed inflasks, then sterilized at 121° C. for 15 min. The aging was monitoredat 40° C. (Table III and FIG. 7) and the average size of the particlesis measured by photosedimentation.

Composition of the reference emulsion (for 100 mL).

    ______________________________________                                        Composition         Grams                                                     ______________________________________                                        F-44E               90                                                        Lecithin            4                                                         NaHPO.sub.4 --Na.sub.2 PO.sub.4                                                                   54 mM - 15.3 mM                                           H.sub.2 O for injection                                                                           41.2                                                      ______________________________________                                    

Example 7 Stabilization of an Emulsion of 1,2-Bis(F-Butyl)Ethene(F-44E)/Lecithin by Addition of C₈ F₁₇ CH═CHC₈ H₁₇ (F8H8E)

4 g of egg-yolk lecithin and a mixture of salts of the above compositionwere dispersed in 39.94 mL of injectable water at 30-40° C. F8H8E (2.05mL) was slowly added to this dispersion, which is stirred for 2 min(8000 t/min). 1,2-bis(F-butyl)ethene (F-44E) (54 mL) was then slowlyadded to the F8H8E/lecithin mixture under nitrogen. The whole wasemulsified for 10 min at 24000 t/min at 30-40° C. The coarse emulsionwas transferred under nitrogen into the microfluidizer and after 12passes (12000 psi, 35° C.) the emulsion was sterilized and stored at 40°C. (Table III and FIG. 7).

Example 8 Stabilization of an Emulsion of 1,2-bis(F-butyl)ethene(F-44E)/Lecithin/Water by Addition of C₆ F₁₃ C₁₂ H₂₅ (F6H12)

The protocol described in example 7 was used with 39.9 mL of water 2 mLof F6H12, 4 g of lecithin and 54 mL of perfluorooctyl bromide. Aftermicrofluidization the emulsion was sterilized and stored at 5, 25 and40° C. (Table III and FIG. 8).

                                      TABLE III                                   __________________________________________________________________________    Comparison of stability over time, at 40° C., of                       1,2-bis(F-butyl)ethene (F-44E)/lecithin 90/4% w/v containing                  R.sub.f WR.sub.H and without.                                                                                   after 3                                     Formulation of emulsions                                                                     at    after after 12                                                                             months                                      F-44/lecithine/R.sub.f WR.sub.H % w/v                                                        preparation                                                                         sterilization                                                                       days at 40° C.                                                                at 40° C.                            __________________________________________________________________________    Ref D: 90/4/0  0.14  0.15  0.17   0.32                                        Example 7: 90/4/2.34 (F6H8E)                                                                 0.13  0.14  0.13   0.14                                        Example 8: 90/4/2.85 (F8H8E)                                                                 0.14  0.15  0.16                                               __________________________________________________________________________

It is seen that the addition of small quantities of compounds R_(F)--W--R_(H) to the formula of concentrated fluorocarbon emulsions resultsin strong stabilization, because the size of the fluorocarbon dropletsincreases significantly more slowly (compare in particular the averagediameters of the droplets after 12 days and 3 or 4 months) in theemulsions containing these mixed compounds than in the referenceemulsion which contains none.

EXAMPLE 9 Facilitation of Emulsification of Perfluorooctyl Bromide byAddition of C₈ F₁₇ CH═CHC₈ H₁₇ (F8H8E)

Reference Emulsion E: Emulsion of Perfluorooctyl Bromide (90/4/% w/v)

The protocol described in Example 1 was used. The average particle sizewas measured during microfluidization after 1, 2, 3, 4, 5, 7 and 10passes. The percentage of fine particles (d<0.12 μm) and of coarseparticle (d>0.6 μm) was evaluated. Results are reported in FIG. 9.

Example 9 Effect of the Addition of C₈ F₁₇ CH═CHC₈ H₁₇ (F8H8E) on theEmulsification of Perfluorooctyl Bromide

The same protocol as for reference emulsion E was used but for theaddition of (F8H8E) as described in example 2. Results are shown in FIG.9. It is seen that upon the addition of small amounts of the mixedfluorocarbon-hydrocarbon amphiphilic compounds small emulsion droplets(smaller than 0.12 μm) are formed more rapidly. The number of dropletslarger than 0.6 μm is reduced faster and lower average particle size isattained faster.

The invention may be embodied in other specific forms without departingfrom its spirit or essential characteristics. The described embodimentsare to be considered in all respects only as illustrative and notrestrictive, and the scope of the invention is, therefore, indicated bythe appended claims rather than by the foregoing description. Allmodifications which come within the meaning and range of the lawfulequivalency of the claims are to be embraced within their scope.

What is claimed is:
 1. A composition in the form of an oil-in-wateremulsion, comprising:a continuous aqueous phase; and a discontinuousphase comprising:an amphiphilic surfactant with a hydrophilic part and alipophilic part, or a mixture of such surfactants; 0.01-10% w/v of alipophilic/fluorophilic compound with a lipophilic part and afluorophilic part wherein said lipophilic part comprises a linear,branched or cyclic saturated or unsaturated alkyl group having between 4and 18 carbon atoms, the lipophilic/fluorophilic compound being presentin an effective molar ratio to the surfactant to impart the compositionwith enhanced particle size stability; and a fluorocarbon liquid,wherein said fluorocarbon liquid is different than saidlipophilic/fluorophilic compound; wherein the discontinuous phase is inthe form of discrete droplets of said fluorocarbon liquid comprising anouter layer of the amphiphilic surfactant oriented such that thehydrophilic part thereof is substantially associated with and thelipophilic part thereof is substantially associated with the lipophilicpart of the stabilizing compound, the fluorophilic part of thestabilizing compound being substantially associated with thefluorocarbon liquid.
 2. A composition according to claim 1,comprising:an oily dispersed fluorocarbon-containing phase in aconcentration of from about 10 to 130% weight/volume; and an amphiphilicsurfactant in a concentration of from about 0.05% to 10% weight/volume.3. The composition of claim 2 wherein said lipophilic/fluorophiliccompound and said surfactant are in a molar ratio that is 1:5 to 3:1. 4.A composition according to claim 1 wherein the lipophilic/fluorophiliccompound is of the formula:

    R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I)

wherein R_(F) ¹ is a linear, branched or cyclic C₂₋₁₄ fluorocarbongroup; R_(H) ¹ is a linear, branched or cyclic C₄₋₁₈ saturated orunsaturated hydrocarbon group; and W is absent or is a bivalent speciesselected from the group consisting of --O--, --S--, ##STR6## wherein X¹,X² and X³ are absent or are independently selected from the groupconsisting of --O-- and --S--; R_(F) ² is a fluorocarbon independentlyselected from the group defined for R_(F) ¹ ; R_(H) ² is a hydrocarbonindependently selected from the group defined for R_(H) ¹ ; R² is absentor is selected from the group consisting of fluorocarbon radicals andhydrocarbon radicals wherein said fluorocarbon radicals and saidhydrocarbon radicals are independently selected from the group definedfor R_(F) ¹ and the group defined for R_(H) ¹ ; and p and q areindependently 1-10; provided that R_(F) ¹ and R_(F) ² comprise at least4 fluorine atoms, and correspond to a hydrocarbon analogue whereinfluorine atoms replace from 50% to 100% of the hydrogen atoms.
 5. Acomposition according to claim 4, wherein R_(F) ¹ is CF₃ (CF₂)_(t) --and wherein t=1 to
 11. 6. A composition according to claim 4, whereinsaid lipophilic/fluorophilic compound is of the formula:

    CF.sub.3 (CF.sub.2).sub.t1 --(CH.sub.2).sub.t2 --CH═CH--(CH.sub.2).sub.y --CH.sub.3

wherein t₁ =2 to 11, t₂ =0 or 1 to 6 and y=1 to
 15. 7. A compositionaccording to claim 6, wherein t₂ =0; t₁ =3, 5, or 7, and y=5, 7, 9, or11.
 8. A method for stabilizing the particle size of emulsions having anaqueous continuous phase, a fluorocarbon disperse phase and containing ahydrophilic/lipophilic surfactant, comprising the step of adding to theemulsion an effective particle size-stabilizing amount of alipophilic/fluorophilic compound wherein the lipophilic/fluorophiliccompound is different than the fluorocarbon and wherein thelipophilic/fluorophilic compound is of the formula

    R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I)

prior to emulsification wherein R_(F) ¹, W, and R_(H1) are as defined inclaim 4 prior to emulsification; and the lipophilic/fluorophiliccompound is added so as to comprise 0.01-10% w/v of the emulsion.
 9. Themethod of claim 8, wherein the molar ratio of saidlipophilic/fluorophilic compound to said surfactant is 1:5 to 3:1. 10.The method of claim 8 wherein the surfactant is egg yolk phospholipid(EYP) and the molar ratio of said lipophilic/fluorophilic compound toEYP is 1:5 to 2:1.
 11. A method for adjusting the particle size influorocarbon emulsions, comprising the steps of:providing an emulsionformulation comprising a fluorocarbon component, ahydrophilic/lipophilic surfactant, an aqueous component; and 0.01-10%w/v of a lipophilic/fluorophilic compound of the formula

    R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I)

wherein R_(F) ¹, W, and R_(H) ¹ are as defined in claim 4, so that themolar ratio of said lipophilic/fluorophilic compound to saidhydrophilic/lipophilic surfactant is 1:5 to 3:1 and wherein saidlipophilic/fluorophilic compound is different than said fluorocarboncomponent; and emulsifying said emulsion formulation to form afluorocarbon emulsion.
 12. A composition in the form of an oil-in-wateremulsion, comprising:an oily disperse phase comprising at least onefluorocarbon or highly fluorinated compound; an aqueous phase; ahydrophilic/lipophilic surfactant; and 0.01 to 10% w/v of alipophilic/fluorophilic compound wherein said lipophilic/fluorophiliccompound is different than said fluorocarbon or highly fluorinatedcompound and wherein the lipophilic/fluorophilic compound is of theformula:

    R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I)

wherein R_(F) ¹ is a linear, branched or cyclic C₂₋₁₄ fluorocarbongroup; R_(H) ¹ is a linear, branched or cyclic C₄₋₁₈ saturated orunsaturated hydrocarbon group; and W is absent, a bivalent speciesselected from the group consisting of --O-- and --S--, or is selectedfrom the group consisting of: ##STR7## wherein X¹, X² and X³ are absentor are independently selected from the group consisting of --O-- and--S--; R_(F) ² is a fluorocarbon independently selected from the groupdefined for R_(F) ¹ ; R_(H) ² is a hydrocarbon independently selectedfrom the group defined for R_(H) ¹ R² is absent or is a fluorocarbon ora hydrocarbon radical independently selected from the group defined forR_(F) ¹ or the group defined for R_(H) ¹ ; p and q are independently1-10; and R_(F) ¹ and R_(F) ² comprise at least 4 F atoms, andcorrespond to a hydrocarbon analogue wherein F atoms replace from 50% to100% of the hydrogen atoms in the carbon chain.
 13. A composition in theform of an oil-in-water, emulsion, comprising:an oily disperse phasecomprising at least one fluorocarbon or highly fluorinated compound; acontinuous aqueous phase; a hydrophilic/lipophilic surfactant; and 0.01to 50% w/v of a lipophilic/fluorophilic compound wherein saidlipophilic/fluorophilic compound is different than said fluorocarbon orhighly fluorinated compound and wherein the lipophilic/fluorophiliccompound is of the formula: ##STR8## wherein X⁴ is --O--, --S-- or--S--S--; and a1 and a2 are independently from 0 to 11; or a mixture ofsaid compounds; R_(F) ¹ is a linear, branched or cyclic C₂₋₁₄fluorocarbon group; R_(H) ¹ is a linear, branched or cyclic C₁₋₁₈saturated or unsaturated hydrocarbon group; R_(F) ² is a fluorocarbonindependently selected from the group defined for R_(F) ¹ ; R_(H) ² is ahydrocarbon independently selected from the group defined for R_(H) ¹ ;provided that R_(F) ¹ and R_(F) ² comprise at least 4 F atoms, andcorrespond to a hydrocarbon analogue wherein F atoms replace from 50% to100% of the hydrogen atoms in the carbon chain.
 14. A composition in theform of an oil-in-water emulsion, comprising:an oily disperse phasecomprising at least one fluorocarbon or highly fluorinated compound; acontinuous aqueous phase; a hydrophilic/lipophilic surfactant; and 0.01to 50% of a lipophilic/fluorophilic compound wherein saidlipophilic/fluorophilic compound is different than said fluorocarbon orhighly fluorinated compound and wherein said lipophilic/fluorophiliccompound is of the formula ##STR9## wherein X⁵ is --O--, --S--, or--S--S--; p and q are independently from 1 to 10; R_(F) ¹ and R_(F) ²are independently selected from a group of perfluoroalkylated radicalshaving from 2 to 10 carbon atoms, and R_(H) ³ is selected from the groupof consisting of hydrocarbon radicals having from 2 to 16 carbon atomsand a mixture of said compounds.
 15. A composition according to any ofclaims 12-14 or 4 wherein R_(F) ¹ and R_(F) ² are independently selectedfrom the group consisting of:CF₃ (CF₂)t-- wherein t=1 to 11;(CF₃)₂CF(CF₂)_(v) -- wherein v=0 to 8; CF₃ --(CF₂ CF(CF₃))_(w) -- wherein w=1to 4; C₂ F₅ --(CF₂ CF(CF₃))_(w) -- wherein w=1 to 4; (CF₃)₂ (CF--CF₂CF(CF₃))_(w) -- wherein w=1 to 3; and ##STR10## wherein x=1 to 6; andR_(F) ¹ and R_(F) ² are independently chosen from the group consistingof CF₃ --, C₂ F₅ --, n--C₃ F₇ -- and CF₃ CF₂ CF(CF₃)--; orR_(F) ¹ andR_(F) ² together form a bivalent radical chosen from the groupconsisting of: --CF₂ (CF₂)₂ CF₂ --; --CF₂ (CF₂)₃ CF₂ --; and CF₃ CF₂O--(CF₂ CF₂ O)_(y) --CF₂ --, wherein y=0 to 3; and CF₃ (CF₂)₂O--(CF(CF₃))(CF₂ O)_(y) --CF(CF₃)--, wherein y=0 to
 2. 16. A compositionaccording to any of claims 12, 13 or 4, wherein R_(H) ¹ and R_(H) ² areindependently selected from the group consisting of:(a) CH₃ --(CH₂)_(y1)--, wherein y1=3 to 17; (b) CH₃ (CH₂)_(y2) (CH═CH)q(CH₂)_(y3) -- and CH₃(CH₂)_(y2) --S--(CH₂)_(y3) -- wherein y2 and y3 are independently 1 to16, and q=0 or 1; (c) CH₃ (CH₂ --CH₂ --O)_(y4) --CH₂ -- wherein y4=1 to8; and (d) CH₃ (CH(CH₃)CH₂ O)_(y5) --CH--CH₃ wherein y5=1 to
 5. 17. Acomposition according to any of claims 12 or 4, wherein:R_(H) ¹ is R⁴--CH═CH--(CH₂)_(p) --, wherein R⁴ is a C₄₋₁₂ alkyl group, and p=0 or 1to 8, provided however R⁴ and (CH₂)_(p) comprise 16 or less carbonatoms, and W is absent.
 18. A composition according to any of claims 12or 4, wherein:R_(H) ¹ is a straight chain C₄₋₁₄ alkyl group, and W isabsent.
 19. A composition according to claim 12 or 4, wherein:R_(H) ¹ isa, straight chain C₄₋₁₂ alkyl group, and W is a group of formula:##STR11## wherein X¹, X², X³ are absent or are independently selectedfrom the group consisting of --O-- and --S--, R² is absent and R_(H) ²is a hydrocarbon independently selected from the group defined for R_(H)¹.
 20. A composition according to any one of claims 12-14, 1 or 4,wherein said fluorocarbon is selected from the group consisting ofperfluorodecalin, perfluorooctylbromide, 1,2-bis-(F-alkyl)-ethenes,perfluoromethyldecalins, perfluorodimethyldecalins,perfluoromethyladamantanes, perfluorodimethyladamantanes,perfluoromethylbicyclo (3,3,1) nonanes, perfluorodimethylbicyclo (3,3,1)nonanes, trimethylbicyclo (3,3,1) nonanes,perfluoroperhydrophenanthrenes, ethers selected from the groupconsisting of (CF₃)₂ CFO(CF₂ CF₂)₂ OCF(CF₃)₂, (CF₃)₂ CFO(CF₂ CF₂)₃OCF(CF₃)₂, (CF₃)₂ CFO(CF₂ CF₂)₂ F, (CF₃)₂ CFO(CF₂ CF₂)₃ F, F(CF(CF₃)CF₂O)₂ CHFCF₃ and (CF₃ CF₂ CF₂ (CF₂)_(u))₂ O with u=1, 3 or 5, aminesselected from the group consisting of N(C₃ F₇)₃, N(C₄ F₉)₃ and N(C₅F₁₁)₃, perfluoro-N-methylperhydroquinolines,perfluoro-N-methylperhydroisoquinolines, perfluoroalkyl hydrides, andhalogenated derivatives selected from the group consisting of C₆ F₁₃ Br,C₈ F₁₇ Br, C₆ F₁₃ CBr₂ CH₂ Br, 1-bromo 4-perfluoroisopropyl cyclohexane,C₈ F₁₆ Br₂, CF₃ CF₂ CF₂ --C(CF₃)₂ --CH₂ CH₂ CH₂ --CF(CF₃)₂ and CF₃ O(CF₂CF₂ O)_(u) CF₂ --CH₂ OH with u=2 or
 3. 21. A composition according toclaim 20, wherein said fluorocarbon is perfluorooctyl bromide.
 22. Acomposition according to claim 20, wherein said fluorocarbon is a1,2-bis-(F-alkyl)ethene selected from the group consisting ofbis(F-butyl)-1,2-ethenes, F-isopropyl-1-F-hexyl-2-ethenes and thebis(F-hexyl)-1,2-ethenes.
 23. A composition according to claim 20,wherein said fluorocarbon is perfluorodecalin.
 24. A composition in theform of an oil-in-water emulsion, comprising:a disperse oily phasecomprising at least one fluorocarbon or highly fluorinated compound; acontinuous aqueous phase; a hydrophilic/lipophilic surfactant; and0.01-50% of a lipophilic/fluorophilic compound, wherein saidlipophilic/fluorophilic compound is different than said fluorocarbon orhighly fluorinated compound, and wherein the lipophilic-fluorophiliccompound is of the formula:

    R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I)

wherein R_(F) ¹ is a linear, branched or cyclic C₂₋₁₄ fluorocarbon groupR_(H) ¹ is a straight chain C₄₋₁₂ alkyl group, and W is O or S or amixture of said compounds.
 25. A composition in the form of anoil-in-water, emulsion, comprising:an oily disperse phase comprising atleast one fluorocarbon or highly fluorinated compound; a continuousaqueous phase; a surfactant; and 0.01-50% of a lipophilic/fluorophiliccompound, wherein said lipophilic/fluorophilic compound is differentthan said fluorocarbon or highly fluorinated compound, and wherein thelipophilic-fluorophilic compound is of the formula:

    R.sub.F.sup.1 --W--R.sub.H.sup.1                           (I)

wherein R_(F) ¹ is a linear, branched or cyclic C₂₋₁₄ fluorocarbongroup; R_(H) ¹ is a straight chain C₄₋₁₂ alkyl group, and W is a groupof formula: ##STR12## wherein X¹, X², X³ are absent or are independentlyselected from the group consisting of --O-- or --S--; and R_(F) ² is afluorocarbon independently selected from the group defined for R_(F) ¹.26. A composition according to any of claims 12-14, 24, 25, 1, or 4,further comprising a physiologically effective additive selected fromthe group consisting of mineral salts, buffering agents, osmotic agents,oncotic agents, pharmaceutical products, nutritive products, anddiagnostic agents.
 27. A composition according to any of claims 12-14,24, 25, 1 or 4 wherein said hydrophilic/lipophilic surfactant isselected from the group consisting of phospholipids andpolyoxyethylene-polyoxypropylene type surfactants and their mixtures.28. A composition according to any of claims 12-14, 24, 25, 1 or 4wherein said hydrophilic/lipophilic surfactant is egg yolk phospholipid(EYP).
 29. A composition according to claim 28 wherein the ratio of saidlipophilic/fluorophilic compound to EYP is between about 1:2 and 2:1.